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Cite this: Chem. Commun., 2014, 50, 13391

A highly efficient dual catalysis approach for C-glycosylation: addition of (o-azaaryl)carboxaldehyde to glycals†

Received 5th August 2014, Accepted 12th September 2014

Yaguang Bai, Wei Lin Leng, Yongxin Li and Xue-Wei Liu*

DOI: 10.1039/c4cc06111j www.rsc.org/chemcomm

A novel and efficient dual catalysis approach by concurrent activation of glycals and (o-azaaryl)-carboxaldehydes using palladium and N-heterocyclic carbene has been developed. The two electrophiles could react after activation through formation of the Breslow intermediate and a p-allyl Pd complex, widening the scope of reacting glycosylation partners and opening up possibilities for future glycosylation.

Dual catalysis is an emerging field in catalytic chemistry, which has attracted increasing attention because of its promising potential extension to many seemingly unreactive reactants, through concurrent activation of an electrophile and a nucleophile (Fig. 1).1 Despite the useful application of dual catalysis, it is still uncommonly explored due to the prerequisite of having two catalysts that are compatible under the reaction conditions.2 In particular, the organo catalyst-metal combination for cooperative dual catalysis has attracted much interest. So far, the most commonly used electrophiles are the cationic organometallic complexes activated by transition metal catalysts such as palladium,3 ruthenium,4 and iridium5 while nucleophiles include vanadium-allenoates,3b enamines3a,c,d,f,g,4a,5and enones.3e The translation of dual catalysis to carbohydrate chemistry would be an important advancement to current glycosylation methods by allowing a wider range of substrates to react with glycals upon activation. Our synthetic methodology would be

Fig. 1

especially significant because of the importance of C-glycoside products,6 due to their activity in enzymatic and metabolic chemistry,7 frequent occurrence in natural products8 and potential to serve as chiral building blocks in synthetic chemistry.9 Our strategy is to combine the two seemingly unreactive electrophilic reactants, aldehydes and glycals, to form C-glycosides. This would be made possible by the N-heterocyclic carbene catalyzed umpolung of aldehyde to form the Breslow intermediate to attack the electrophilic p-allyl Pd complex.10 However, the challenge is the selective attack of the p-allyl Pd complex instead of aldehyde starting material upon umpolung activation. This is particularly so as the resulting Pd-glycal complexes11 are substantially electrophilic and are reported to be able to react with a variety of nucleophiles, such as enolates,11a imidazoles,11b alcohols and phenols.11c Encouraged by our recent discovery,12 we envisaged that the dual catalyzed C-glycosylation reactions of glycals and (o-azaaryl)carboxaldehydes (Fig. 2) could proceed, driven by the faster reaction rate and higher affinity between the two activated species than the activated species with the reactant. Our initial effort began with the coupling of 3-(ethoxycarbonyloxy)-4,6-para-methoxybenzylidene-D-glucal 1a and pyridine2-carboxaldehyde 2a in the presence of Pd(PPh3)4, 5-(2-hydroxyethyl)3,4-dimethylthiazolium iodide and triethylamine in DCM at 50 1C

Cooperative catalysis through dual activation.

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371. E-mail: [email protected] † Electronic supplementary information (ESI) available: General experimental procedures and spectral charts of all products. See DOI: 10.1039/c4cc06111j

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Fig. 2

Dual catalysis of the allylic system and the Breslow intermediate.

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Table 1

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Optimization conditionsa

Entry Pd source Ligand Base 1 2 3 4 5 6 7 8 9 10 11 12 13c

Pd(PPh3)4 Pd(PPh3)4 Pd(OAc)2 Pd(TFA)2 Pd(PPh3)4 Pd2(dba)3 Pd(dba)2 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3 Pd2(dba)3

— DPPB DPPB DPPB DiPPF DiPPF DiPPF DtBPF DtBPF DtBPF DtBPF DtBPF DtBPF

NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 NEt3 DBU Cs2CO3 K2CO3 DBU

Table 2

Solvent

T (1C) Yield 3a (4)b (%)

DCM DCM DCM DCM DCM DCM DCM DCM Toluene Toluene Toluene Toluene Toluene

50 50 50 50 50 50 50 50 80 80 80 80 80

Substrate scope of aldehydesa,b

0 (0) 20 (22) Trace (25) 0 (o5) 35 (50) 45 (38) 24 (45) 57 (23) 71 (10) 85 (o5) 40 (15) 62 (12) 75 (o5)

a

Unless otherwise specified, reactions were carried out with 1.5 equivalent aldehyde, 1 equivalent base, 10 mol% Pd catalyst, 15 mol% ligand, 20 mol% NHC. b Isolated yield. c This reaction was carried out with 2.5 mol% Pd2(dba)3 and 7.5 mol% DtBPF. DPPB: 1,4-bis(diphenylphosphino)butane, DiPPF: 1,10 -bis-(diisopropyl-phosphino)-ferrocene, DtBPF: 1,10 -bis(ditertbutylphosphino)-ferrocene.

(Table 1, entry 1). No new compound was observed after 48 hours. Upon addition of the DPPB ligand while keeping the other conditions constant, we managed to obtain the desired C-glycoside 3a in 20% yield (Table 1, entry 2). However, the corresponding O-glycoside 4 was also isolated in 22% yield since the nucleophilic ethanol was generated during the decarboxylative step. Delighted with this finding, we went on to screen other commonly used palladium catalysts. The results showed that Pd(II) catalysts such as palladium acetate (Table 1, entry 3) and palladium trifluoroacetate (Table 1, entry 4) barely gave any desired product. On the other hand, attempts by using Pd(0) catalysts with a better ligand DiPPF (Table 1, entries 5–8) revealed that Pd2(dba)3 was the best Pd source. Further screening of ligands showed that DtBPF (Table 1, entry 8) was able to give a higher yield. The use of toluene as solvent and increase of temperature to 80 1C (Table 1, entry 9) gave more than 70% yield. Screening of bases commonly used in NHC catalyzed reactions (Table 1, entries 10–12) indicated that DBU was the most suitable base for this coupling reaction. When the loading of the Pd catalyst and the ligand was decreased, the yield was greatly affected (Table 1, entry 13). After obtaining the optimized reaction conditions, we proceeded to explore the substrate scope for both (o-azaaryl)carboxaldehydes and glycals. The substrate scope of aldehydes is summarized in Table 2. The structure of the C-glycoside 3a was confirmed by X-ray crystallography.13 A group of methyl substituted pyridine-2carboxaldehydes were first tested. It was observed that the methyl substituents on 4, 5 and 6 positions could afford the desired products in good yields (3b, 3c, 3d) but this was not the case when 3-methyl-2-pyridine carboxaldehyde was used.14 2-Pyridine carboxaldehydes with electron-donating groups such as methoxyl (3e) and thiophenyl (3f) also generally provided the products in good yields.

13392 | Chem. Commun., 2014, 50, 13391--13393

a

Reactions were carried out with 1.5 equivalent aldehyde, 1 equivalent DBU, 5 mol% Pd2(dba)3 catalyst, 15 mol% DtBPF, 20 mol% NHC. b Isolated yield.

In contrast, aldehydes with electron-withdrawing groups such as chloro (3g) and trifluoromethyl (3h) gave only poor to moderate yields. Besides pyridine-2-carboxaldehydes, other o-azaaryl-carboxaldehydes were also synthesized and examined. It was found that quinoline-2carboxaldehyde (3i), isoquinoline-1-carboxaldehyde (3j) and isoquinoline-3-carboxaldehyde (3k) gave the corresponding C-glycosides in slightly lower yields than 2-pyridine-carboxaldehyde, which could be attributed to greater steric hindrance. Several 3-ethoxycarbonyloxy glucals with different 4,6-protecting groups were then treated with 2-pyridine carboxaldehyde under standard conditions (Table 3). The results showed that the acetal protecting groups such as isopropylidene (3l) benzylidene (3m) and cyclohexylidene (3n) could afford the desired C-glycosides in good to excellent yields. The plausible mechanism is proposed in Scheme 1. The formation of a nucleophilic Breslow intermediate and an electrophilic

Table 3

Substrate scope of glycalsa,b

a

Reactions were carried out with 1.5 equivalent aldehyde, 1 equivalent DBU, 5 mol% Pd2(dba)3 catalyst, 15 mol% DtBPF, 20 mol% NHC. b Isolated yield.

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3

Scheme 1

Plausible mechanism.

4

p-allyl Pd complex was catalyzed by NHC and Pd(0) catalysts respectively. These intermediates were brought to close spatial proximity by N–Pd coordination to form intermediate 5. An intramolecular nucleophilic addition then took place between the allylic system and the NHC activated aldehyde part to form intermediate 6. After the regeneration of the NHC catalyst, C-glycoside 7 was released and proton transfer under basic conditions yielded the final product 3a. In summary, a novel dual catalyzed C-glycosylation method of glycals and (o-azaaryl)carboxaldehydes has been developed. The substrate scope included various types of (o-azaaryl)carboxaldehyde and glycals with different protecting groups. This efficient approach for C-glycosylation would expand the range of coupling partners for glycosylation and allow useful and diverse functionalization of glycals for further transformation. Exploration of potential biological activity and further functionalization of the product are ongoing in our laboratory. This work was supported by funding from Nanyang Technological University (RG6/13) and the Ministry of Education, Singapore (MOE2013-T3-1-004).

Notes and references 1 C. Zhong and X. Shi, Eur. J. Org. Chem., 2010, 2999. 2 Examples of catalyst poisoning – NHC as the ligand in palladium chemistry. (a) G. C. Fortman and S. P. Nolan, Chem. Soc. Rev., 2011,

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5 6

7 8

9 10 11

12 13 14

´lez and S. Nolan, N-Heterocyclic 40, 5151; (b) F. Glorius, S. Dı´ez-Gonza Carbenes in Transition Metal Catalysis, Topics in Organometallic Chemistry, Springer, Berlin, Heidelberg, 2007, vol. 21, p. 47; (c) N. M. Scott and S. P. Nolan, N-Heterocyclic Carbenes in Synthesis, Wiley-VCH, 2006, p. 55. ´rdova, Angew. Chem., 2006, 118, 1986 (Angew. (a) I. Ibrahem and A. Co Chem., Int. Ed., 2006, 45, 1952); (b) B. M. Trost and X. Luan, J. Am. Chem. Soc., 2011, 133, 1706; (c) S. Afeweki, I. Ibrahem, J. Rydfjord, ´rdova, Chem. – Eur. J., 2012, 18, 2972; P. Breistein and A. Co (d) S. Mukherjee and B. List, J. Am. Chem. Soc., 2007, 129, 11336; (e) B. G. Jellerichs, J.-R. Kong and M. J. Krische, J. Am. Chem. Soc., 2003, 125, 7758; ( f ) M. Li, S. Datta, D. M. Barber and D. J. Dixon, Org. Lett., 2012, 14, 6350; (g) X. Zhao, D. Liu, H. Guo, Y. Liu and W. Zhang, J. Am. Chem. Soc., 2011, 133, 19354. (a) M. Ikeda, Y. Miyake and Y. Nishibayashi, Angew. Chem., 2010, 122, 7295 (Angew. Chem., Int. Ed., 2010, 49, 7289); (b) D. A. Nicewicz and D. W. C. MacMillan, Science, 2008, 322, 77. S. Krautwald, D. Sarlah, M. A. Schafroth and E. M. Carreira, Science, 2013, 340, 1065. For examples of C-glycosylation catalyzed by transition metals, see (a) F. Ding, R. William, B. K. Gorityala, J. Ma, S. Wang and X.-W. Liu, Tetrahedron Lett., 2010, 51, 3146; (b) H.-H. Li and X.-S. Ye, Org. Biomol. Chem., 2009, 7, 3855; (c) D.-C. Xiong, L.-H. Zhang and X.-S. Ye, Org. Lett., 2009, 11, 1709; (d) S. H. Xiang, S. T. Cai, J. Zeng and X.-W. Liu, Org. Lett., 2011, 13, 4608; (e) C.-F. Liu, D.-C. Xiong and X.-S. Ye, J. Org. Chem., 2014, 79, 4676. (a) P. G. Hultin, Curr. Top. Med. Chem., 2005, 5, 1299; (b) Z. Wei, Curr. Top. Med. Chem., 2005, 5, 1363. (a) D. T. Connor, R. C. Greenough and M. Von Strandtmann, J. Org. Chem., 1977, 42, 3664; (b) K. Kito, R. Ookura, S. Yoshida, M. Namikoshi, T. Ooi and T. Kusumi, Org. Lett., 2007, 10, 225; (c) J. Malmstrøm, C. Christophersen, A. F. Barrero, J. E. Oltra, J. Justicia and A. Rosales, J. Nat. Prod., 2002, 65, 364. (a) T. Nagasawa and S. Kuwahara, Org. Lett., 2009, 11, 761; (b) T. Nishikawa, Y. Koide, A. Kanakubo, H. Yoshimura and M. Isobe, Org. Biomol. Chem., 2006, 4, 1268. (a) T. Nemoto, T. Fukuda and Y. Hamada, Tetrahedron Lett., 2006, 47, 4345; (b) R. Lebeuf, K. Hirano and F. Glorius, Org. Lett., 2008, 10, 4243. For examples of Tsuji–Trost type C-glycosylation, see: (a) J. Zeng, J. Ma, S. Xiang, S. Cai and X.-W. Liu, Angew. Chem., Int. Ed., 2013, 52, 5134; (b) S. Xiang, J. He, J. Ma and X.-W. Liu, Chem. Commun., 2014, 50, 4222; (c) S. Xiang, Z. Lu, J. He, K. Le Mai Hoang, J. Zeng and X.-W. Liu, Chem. – Eur. J., 2013, 19, 14047. Y. Bai, S. Xiang, M. L. Leow and X.-W. Liu, Chem. Commun., 2014, 50, 6168. See ESI† for the details of the X-ray crystallography. C. E. Houlden, C. D. Bailey, J. G. Ford, M. R. Gagne, G. C. Lloyd-Jones and K. I. Booker-Milburn, J. Am. Chem. Soc., 2008, 130, 10066.

Chem. Commun., 2014, 50, 13391--13393 | 13393

A highly efficient dual catalysis approach for C-glycosylation: addition of (o-azaaryl)carboxaldehyde to glycals.

A novel and efficient dual catalysis approach by concurrent activation of glycals and (o-azaaryl)-carboxaldehydes using palladium and N-heterocyclic c...
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